Maintenance of tissue homeostasis by adult stem cells is critical to preserve the functional integrity of long- lived organisms. Thus, the mechanisms that control all aspects of stem cell biology during adult life have to be accurately regulated. Particularly, stem cell proliferation rate has to be adapted to context-dependent demands. Previous research in the field has concentrated on the mechanisms that induce proliferation and/or the expansion of stem and progenitor pools. It has to be recognized, however, that throughout the lifespan of an organism, most tissue-specific stem and progenitor populations will undergo multiple transient periods of regenerative activity, for example after acute tissue damage or injury. These periods are followed by re-entry into a quiescent state. In addition to studying stem cell activation, it is therefore also critical to understand the mechanisms that promote stem cell quiescence. Defects in these mechanisms are likely to have deleterious long-term effects on tissue homeostasis, such as uncontrolled proliferation and hyperplasia, or exhaustion of the stem cell pool and loss of regenerative capacity. The Drosophila intestinal stem cell (ISC) population is a very powerful model to study the conserved mechanisms that regulate stem cell biology in a genetically accessible organism. The Tis11 protein was recently identified as a factor that is specifically required for the restoration of IS quiescence after a proliferative period of tissue repair. Tis11 is a member of a conserved RNA binding protein family that negatively regulates the stability of mRNAs containing AU-rich elements (ARE). Interestingly, recent studies have implicated the Tis11 protein family into the regulation of mammalian stem cell and progenitor populations. However, the precise role of Tis11-related proteins in these cells, their potential regulation and their direct targets remain largely unknown. Studies in Drosophila thus provide a unique opportunity to address some of these questions. The proposed work will use genetic and biochemical approaches, as well as innovative reporter systems, to characterize the role of Tis11, and the ARE-mediated mRNA decay pathway, in the control of ISC quiescence and epithelium regeneration. In particular, the experiments described will identify the molecular targets of Tis11 and the potential regulation of its activity in ISCs. In addition, the proposed studies will investigate the possible influence of aging on these mechanisms and investigate the consequences of their deregulation on long-term tissue homeostasis and longevity. Finally, this work will test the possibility of delaying tissue aging and extending lifespan by manipulating Tis11 and the mRNA decay pathway, specifically in somatic stem cells. In the long term, better understanding of the mechanisms that control stem cell quiescence, in particular the Tis11-related proteins, is expected to provide new insights into some of the processes that might drive normal tissue aging, degenerative diseases and cancer.